PCF hosts an Annual Scientific Retreat to share the latest research findings, inspire collaboration, promote mentorship, and honor the newest awardees. Sessions at the 31st Retreat addressed basic biology and genetics research, clinical trials, new drug targets to overcome treatment resistance, the future of AI in prostate cancer, the impact of health habits on outcomes and survivorship, and more.
Part 2 of our Highlights series features advances in:
- Treatment: Advances continue through clinical trials of PSMA-targeted imaging and therapy, including new combinations, sequences, and using 177-Lutetium-PSMA-617 earlier in the disease course
- Research and care for Veterans: A vast, highly detailed, and robust new dataset called VA-MAPP is a powerful tool that now allows researchers to use Veterans’ data to ultimately help advance and improve their care.
- Genetics: Certain inherited changes in the BRCA2 gene can increase a person’s risk of aggressive prostate cancer diagnosis, but are not useful in forecasting survival among patients already diagnosed
Read Part 1 on the latest in prostate cancer, exercise, and nutrition here.
“See It, Treat It”: The Latest on PSMA-Targeting Approaches
Louise Emmett, MD
The University of New South Wales, Australia
Doctors can target Prostate Specific Membrane Antigen (PSMA), a protein on the surface of prostate cancer cells, to see small amounts of prostate cancer anywhere in the body, and treat it by delivering cancer-killing medicines to the cells. Currently, 177-Lutetium-PSMA-617 (Pluvicto®) is FDA-approved for patients with metastatic castration-resistant prostate cancer (mCRPC) whose cancer has worsened after treatment with an androgen receptor pathway inhibitor (ARPI) and with chemotherapy. PCF has invested more than $63M in research in this technology. Recent advances include ways to predict which patients will respond to treatment, and the potential to give this treatment earlier in the disease course.
The TheraP trial compared 177-Lutetium-PSMA-617 to cabazitaxel chemotherapy in men with mCRPC. Both treatments showed similar survival, suggesting 177-Lutetium-PSMA-617 as a viable option. A blood test measuring circulating tumor DNA may help predict who would respond better to this treatment.
The EnzaP trial compared enzalutamide + 177-Lutetium-PSMA-617 vs. enzalutamide alone in patients with mCRPC. After 15 days of enzalutamide, approximately 2/3 of patients showed increased PSMA PET levels, which were linked to poorer responses to enzalutamide alone, but better responses to the combination treatment. These results suggest that adding 177-Lutetium-PSMA-617 can help patients who don’t respond well to enzalutamide alone.
Two phase 3 trials, PSMAFORE and SPLASH, tested similar PSMA-targeted radionuclide therapies vs. a switch in ARPI, earlier in the course of prostate cancer. The results showed that the PSMA-targeted treatment improved outcomes in the trial that used a higher and more frequent dose, but made no difference in the trial that used a lower and less frequent dose of PSMA-targeted radionuclide therapy. This indicates that optimal dosing and treatment schedules are needed to improve patient outcomes.
The Upfront PSMA trial showed promising results combining docetaxel with 177-Lutetium-PSMA-617 in metastatic hormone-sensitive prostate cancer.
Finally, new PSMA-targeted imaging agents, like Copper-64 Sarbis PSMA, are showing promise for early assessment of recurrent prostate cancer.
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Leveraging “Big Data” in the VA to Improve Patient Outcomes
Isla Garraway, MD, PhD
Greater Los Angeles VA Medical Center & UCLA
Many urgent research questions remain unanswered in prostate cancer, such the impact of environmental exposures on prostate cancer risk, how to predict which patients will respond to certain treatments, and drivers of racial disparities. Researchers can analyze large databases to address these questions. The Department of Veterans Affairs (VA)’s extensive electronic health record is the oldest in the U.S., spanning 25 years, and provides rich data on Veterans’ clinical history (including prostate cancer), social determinants of health (e.g., income, race/ethnicity, and neighborhood socioeconomic status), lifestyle, and environmental and military exposures.
To leverage the VA’s extensive data for research on prostate cancer, the VA Multi-omics Analysis Platform for Prostate Cancer (VA-MAPP) was developed (see Figure below). The data platform has two components. One is a collection of data and existing samples from 11 million Veterans at risk of prostate cancer, including over 1 million diagnosed cases and 83,000 with metastatic disease. The second component is prospective collection of samples and data from patients as they undergo prostate cancer diagnosis and treatment through an informed consent process.
Thus far, archival tissues have been retrospectively collected from 2,200 patients and nearly 400 patients have been enrolled for the ongoing data collection piece. These patients reflect the diversity of the VA population, with ~36% having African American ancestry and ~10% of other, non-White races.
VA-MAPP is a powerful tool that allows researchers to use Veterans’ data to ultimately help advance and improve their care.
Ongoing studies using VA-MAPP include investigations to examine the frequency of rare germline prostate cancer risk gene variants, to define the spectrum and frequency of acquired prostate cancer mutations in racially and ethnically diverse populations and identify equitable precision oncology applications, to understand the real-world treatment and outcomes of patients with prostate cancer, and to develop AI models that improve outcome predictions for high-risk prostate cancer patients.
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New Findings on the Importance of Inherited Changes in the BRCA2 Gene
Konrad Stopsack, MD, MPH
Massachusetts General Hospital; Harvard T.H. Chan School of Public Health
An inherited mutation is a change in a parent’s DNA that can be passed down to a child. Changes in genes that function to repair damaged DNA, such as BRCA2, are particularly important in several types of cancer, including prostate, breast, ovarian, and pancreatic. Inherited harmful mutations in the BRCA2 gene are known to increase the risk of diagnosis of aggressive prostate cancer and death from the disease.
Doctors need reliable “biomarkers,” or signals, that can provide information about a patient’s prognosis, (the likely course and outcome of the disease). Whether having a harmful BRCA2 gene change is associated with shorter survival among patients already diagnosed with prostate cancer was unclear.
Dr. Stopsack and colleagues investigated this question in groups of patients diagnosed with high-risk and with metastatic prostate cancer. They found that among patients diagnosed with the same prostate cancer disease state, the presence of harmful BRCA2 gene changes was not associated with a substantially worse prognosis in terms of metastasis-free survival or overall survival.
These data suggest that while BRCA2 gene changes are a strong risk factor for the development of aggressive prostate cancer, and while they can predict response to medicines called PARP-inhibitors, they are not strongly prognostic once the cancer is already present and defined by other clinical features. In counseling patients, is important to know what a particular biomarker reveals about a patient’s disease progression as well as to understand its limitations.